Innate Immunity to Pneumococcal Infection of the Central Nervous System Depends on Toll‐Like Receptor (TLR) 2 and TLR4

The complement system is a highly conserved component of innate immunity that is involved in recognizing and responding to pathogens. The system serves as a bridge between innate and adaptive immunity, and modulation of the complement system can affect the entire host immune response to a foreign insult. Neoplastic diseases have been shown to engage the complement system in order to evade the immune system, gain a selective growth advantage, and co-opt the surrounding environment for tumor proliferation. Historically, the central nervous system has been considered to be an immune-privileged environment, but it is now clear that there are active roles for both innate and adaptive immunity within the central nervous system. Much of the research on the role of immunological modulation of neoplastic disease within the central nervous system has focused on adaptive immunity, even though innate immunity still plays a critical role in the natural history of central nervous system neoplasms. Here, we review the modulation of the complement system by a variety of neoplastic diseases of the central nervous system. We also discuss gaps in the current body of knowledge and comment on future directions for investigation.

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Free Sialic Acid Acts as a Signal That Promotes Streptococcus pneumoniae Invasion of Nasal Tissue and Nonhematogenous Invasion of the Central Nervous System

Infection and Immunity ◽

10.1128/iai.01514-15 ◽

2016 ◽

Vol 84 (9) ◽

pp. 2607-2615 ◽

Cited By ~ 7

Author(s):

Brandon L. Hatcher ◽

Joanetha Y. Hale ◽

David E. Briles

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Streptococcus Pneumoniae ◽

Sialic Acid ◽

Bacterial Meningitis ◽

Imaging System ◽

Pneumococcal Infection ◽

Acute Bacterial Meningitis ◽

Olfactory Bulbs ◽

The Central Nervous System

Streptococcus pneumoniae(pneumococcus) is a leading cause of bacterial meningitis and neurological sequelae in children worldwide. Acute bacterial meningitis is widely considered to result from bacteremia that leads to blood-brain barrier breakdown and bacterial dissemination throughout the central nervous system (CNS). Previously, we showed that pneumococci can gain access to the CNS through a nonhematogenous route without peripheral blood infection. This access is thought to occur when the pneumococci in the upper sinus follow the olfactory nerves and enter the CNS through the olfactory bulbs. In this study, we determined whether the addition of exogenous sialic acid postcolonization promotes nonhematogenous invasion of the CNS. Previously, others showed that treatment with exogenous sialic acid post-pneumococcal infection increased the numbers of CFU recovered from an intranasal mouse model of infection. Using a pneumococcal colonization model, anin vivoimaging system, and a multiplex assay for cytokine expression, we demonstrated that sialic acid can increase the number of pneumococci recovered from the olfactory bulbs and brains of infected animals. We also show that pneumococci primarily localize to the olfactory bulb, leading to increased expression levels of proinflammatory cytokines and chemokines. These findings provide evidence that sialic acid can enhance the ability of pneumococci to disseminate into the CNS and provide details about the environment needed to establish nonhematogenous pneumococcal meningitis.

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The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling

eLife ◽

10.7554/elife.47117 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 14

Author(s):

D Garrett Brown ◽

Raymond Soto ◽

Soumya Yandamuri ◽

Colleen Stone ◽

Laura Dickey ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Oral Administration ◽

Viral Replication ◽

Viral Infection ◽

Host Defense ◽

Toll Like Receptor ◽

Tlr Signaling ◽

The Central Nervous System ◽

The Brain

Symbiotic microbes impact the function and development of the central nervous system (CNS); however, little is known about the contribution of the microbiota during viral-induced neurologic damage. We identify that commensals aid in host defense following infection with a neurotropic virus through enhancing microglia function. Germfree mice or animals that receive antibiotics are unable to control viral replication within the brain leading to increased paralysis. Microglia derived from germfree or antibiotic-treated animals cannot stimulate viral-specific immunity and microglia depletion leads to worsened demyelination. Oral administration of toll-like receptor (TLR) ligands to virally infected germfree mice limits neurologic damage. Homeostatic activation of microglia is dependent on intrinsic signaling through TLR4, as disruption of TLR4 within microglia, but not the entire CNS (excluding microglia), leads to increased viral-induced clinical disease. This work demonstrates that gut immune-stimulatory products can influence microglia function to prevent CNS damage following viral infection.

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